The significant role of interleukin-6 and its signaling pathway in the immunopathogenesis and treatment of breast cancer

Masjedi, Ali; Hashemi, Vida; Hojjat-Farsangi, Mohammad; Ghalamfarsa, Ghasem; Azizi, Gholamreza; Yousefi, Mehdi; Jadidi-Niaragh, Farhad

doi:10.1016/j.biopha.2018.09.177

Cited by 303Cytokine Signaling Pathways and InteractionsBreast Cancer Treatment StudiesImmune cells in cancer

The significant role of interleukin-6 and its signaling pathway in the immunopathogenesis and treatment of breast cancer

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Masjedi, Ali, Hashemi, Vida, Hojjat-Farsangi, Mohammad, Ghalamfarsa, Ghasem, Azizi, Gholamreza, Yousefi, Mehdi, Jadidi-Niaragh, Farhad·2018·Biomedicine & Pharmacotherapy

DOI 10.1016/j.biopha.2018.09.177

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Abstract

Despite remarkable improvements in cancer treatment approaches, breast cancer is still the main cause of cancer-related death in women. Its principal cause is the resistance of the cancer cells against conventional anticancer therapeutics, mainly in advanced disease stages. It has been shown that chronic inflammation in the tumor microenvironment facilitates tumor growth and induces resistance toward chemo- and radiotherapy. Overexpression of interleukin-6 (IL-6) cytokine in the tumor microenvironment has been demonstrated in numerous tumors including breast cancer. Tumor cells and tumor-associated fibroblasts are the major sources of IL-6 secretion in the tumor microenvironment. Several studies have demonstrated the immunopathogenic function of IL-6 and its signaling in the tumor growth, metastasis, and therapeutic resistance in the breast cancer. Therefore, it seems that targeting IL-6 and/or its receptor in combination with other potent anticancer therapies may be a potent therapeutic approach for breast cancer therapy.

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IL-6 is a key factor in inflammation, autoimmunity and cancer, with its effect mainly exerted through the IL-6-STAT3 pathway.
“IL-6 is also a key factor in inflammation, autoimmunity and cancer, with its effect mainly exerted through the IL-6–signal transducer and activator of transcription 3 (STAT3) pathway (18–26, 61–65).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [22]
Section 2 links IL-6 to inflammation, and section 6.2 discusses IL-6 blockade in autoimmune disorders. Sections 3 and 5 describe IL-6/JAK/STAT3 signaling and call STAT3 the most important player in IL-6’s cancer-related functions. The paper does not establish that IL-6’s effects in inflammation and autoimmunity are mainly exerted through STAT3. (LLM, conf=0.82)
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K. Tawara, J.T. Oxford, C.L. Jorcyk, Clinical significance of interleukin (IL)-6 in cancer metastasis to bone: potential of anti-IL-6 therapies, Cancer Manag. Res. 3 (2011) 177-189.

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BackgroundInfluential
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Background
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Pro-Inflammatory Cytokines in the Formation of the Pre-Metastatic Niche
Li, R., Wen, A., & Lin, J. (2020) · Cancers · doi:10.3390/cancers12123752 · Cited by 73 · see citing works
“Various global clinical trials, series, and pilot studies of off-label use of siltuximab and tocilizumab provide strong indications [61] that the anti-IL-6 therapy may be used for the treatment of blood cancers such as multiple myeloma [62] and leukemia [63] and of solid tumors such as prostate cancer [64], breast can…”
Background
Silencing of IL-6 and STAT3 by siRNA loaded hyaluronate-N,N,N-trimethyl chitosan nanoparticles potently reduces cancer cell progression.
Masjedi, A., Ahmadi, A., Atyabi, F., Farhadi, S., Irandoust, M., Khazaei-poul, Y., Chaleshtari, M. G., Fathabad, M. E., Baghaei, M., Haghnavaz, N., et al. (2020) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2020.01.273 · Cited by 68 · see citing works
Self-citation
Retracted
Interleukin-6 serves as a critical factor in various cancer progression and therapy
Mohamed, A. H., Ahmed, A. T., Abdulmonem, W. A., Bokov, D. O., Shafie, A., Al‐Hetty, H. R. A. K., Hsu, C., Alissa, M., Nazir, S., Jamali, M. C., et al. (2024) · Medical Oncology · doi:10.1007/s12032-024-02422-5 · Cited by 68 · see citing works
“It induces several transcription factors that participate in the elevation of immunoglobulin production, acute phase protein production, and improving cell growth in response to environmental and cellular stresses and inflammation [28].”
Effects of IL-6 Signaling Pathway Inhibition on Weight and BMI: A Systematic Review and Meta-Analysis
Patsalos, O., Dalton, B., & Himmerich, H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176290 · Cited by 72 · see citing works
S1PR1 as a Novel Promising Therapeutic Target in Cancer Therapy
Rostami, N., Nikkhoo, A., Ajoolabady, A., Azizi, G., Hojjat-Farsangi, M., Ghalamfarsa, G., Yousefi, B., Yousefi, M., & Jadidi-Niaragh, F. (2019) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-019-00401-5 · Cited by 63 · see citing works
Self-citation
Triple-negative breast cancer influences a mixed M1/M2 macrophage phenotype associated with tumor aggressiveness
Pe, K. C., Saetung, R., Yodsurang, V., Chaotham, C., Suppipat, K., Chanvorachote, P., & Tawinwung, S. (2022) · PLoS ONE · doi:10.1371/journal.pone.0273044 · Cited by 62 · see citing works
“Several tumor cells, including breast cancer cells, can secrete IL-6, the upregulation of which is generally associated with poor prognosis and a low survival outcome [41,42].”
Background
Patterns of immune evasion in triple-negative breast cancer and new potential therapeutic targets: a review
Serrano-García, L., Jávega, B., Llombart‐Cussac, A., Gión, M., Pérez-García, J. M., Cortés, J., & Fernández-Murga, M. L. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1513421 · Cited by 57 · see citing works
Enhancement of PD-L1-attenuated CAR-T cell function through breast cancer-associated fibroblasts-derived IL-6 signaling via STAT3/AKT pathways
Chuangchot, N., Jamjuntra, P., Yangngam, S., Luangwattananun, P., Thongchot, S., Junking, M., Thuwajit, P., Yenchitsomanus, P., & Thuwajit, C. (2023) · Breast Cancer Research · doi:10.1186/s13058-023-01684-7 · Cited by 57 · see citing works
“IL-6 is released by various cells including cancer cells, CAFs, and immune cells [15].”
Background
Architecture of Cancer-Associated Fibroblasts in Tumor Microenvironment: Mapping Their Origins, Heterogeneity, and Role in Cancer Therapy Resistance
Dzobo, K., & Dandara, C. (2020) · OMICS A Journal of Integrative Biology · doi:10.1089/omi.2020.0023 · Cited by 65 · see citing works
“Several pathological conditions display high levels of IL-6 and increased activation of the IL-6-JAK-STA3, including rheumatoid arthritis as well as many cancers (Ku-mari et al., 2016; Masjedi et al., 2018).”
IL-6 Cytokine Family: A Putative Target for Breast Cancer Prevention and Treatment
Felcher, C. M., Bogni, E. S., & Kordon, E. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031809 · Cited by 56 · see citing works
“Association with Her2 or endocrine therapy resistance IL-6 [61,62]”
Background
Immune escape mechanisms and therapeutic approaches in cancer: the cancer-immunity cycle
Starzer, A. M., Preusser, M., & Berghoff, A. S. (2022) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359221096219 · Cited by 54 · see citing works
Naringenin Enhances the Anti-Cancer Effect of Cyclophosphamide against MDA-MB-231 Breast Cancer Cells Via Targeting the STAT3 Signaling Pathway
Noori, S., Tavirani, M. R., Deravi, N., Rabbani, M. I. M., & Zarghi, A. (2020) · Iranian journal of pharmaceutical research · doi:10.22037/ijpr.2020.113103.14112 · Cited by 54 · see citing works
Identification of extracellular matrix proteins secreted by human dermal fibroblasts cultured in 3D electrospun scaffolds
Malakpour-Permlid, A., Buzzi, I., Hegardt, C., Johansson, F., & Oredsson, S. (2021) · Scientific Reports · doi:10.1038/s41598-021-85742-0 · Cited by 51 · see citing works
Structure-based 3D-Pharmacophore modeling to discover novel interleukin 6 inhibitors: An in silico screening, molecular dynamics simulations and binding free energy calculations
Tran, Q., Nguyen, Q.-T., Vo, N., Mai, T., Tran, T.-T.-N., Tran, T.-D., Le, M., Trinh, D., & Thai, K. (2022) · PLoS ONE · doi:10.1371/journal.pone.0266632 · Cited by 49 · see citing works
Cancer-associated fibroblast-like fibroblasts in vocal fold leukoplakia suppress CD8+T cell functions by inducing IL-6 autocrine loop and interacting with Th17 cells.
Fang, Y., Chen, M., Li, G.-F., Yang, Y., He, P., Chen, J., Cheng, L., & Wu, H. (2022) · Cancer Letters · doi:10.1016/j.canlet.2022.215839 · Cited by 47 · see citing works
Roles for macrophage-polarizing interleukins in cancer immunity and immunotherapy
Mortezaee, K., & Majidpoor, J. (2022) · Cellular Oncology · doi:10.1007/s13402-022-00667-8 · Cited by 46 · see citing works
Apigenin Inhibits IL-6 Transcription and Suppresses Esophageal Carcinogenesis
Qiu, J.-G., Wang, L., Liu, W.-J., Wang, J.-F., Zhao, E.-J., Zhou, F.-M., Ji, X.-B., Wang, L.-H., Xia, Z.-K., Wang, W., et al. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01002 · Cited by 43 · see citing works
Silencing STAT3 enhances sensitivity of cancer cells to doxorubicin and inhibits tumor progression.
Joshi, N., Hajizadeh, F., Dezfouli, E. A., Zekiy, A., Afjadi, M. N., Mousavi, S. M., Hojjat-Farsangi, M., Karpisheh, V., Mahmoodpoor, A., Hassannia, H., et al. (2021) · Life Science · doi:10.1016/j.lfs.2021.119369 · Cited by 42
Self-citation
Retracted
Effect of regulatory cell death on the occurrence and development of head and neck squamous cell carcinoma
Xue, Y., Jiang, X., Wang, J., Zong, Y., Yuan, Z., Miao, S., & Mao, X. (2023) · Biomarker Research · doi:10.1186/s40364-022-00433-w · Cited by 42 · see citing works
An Autocrine Wnt5a Loop Promotes NF-κB Pathway Activation and Cytokine/Chemokine Secretion in Melanoma
Barbero, G., Castro, M. V., Villanueva, M. B., Quezada, M. J., Fernández, N., DeMorrow, S., & Lopez‐Bergami, P. (2019) · Cells · doi:10.3390/cells8091060 · Cited by 47 · see citing works
“IL-6, IL-6sR, sTNFRI, and IL-11 are pro-inflammatory cytokines that contribute to angiogenesis, cell proliferation, tumor cell survival, exhaustion of effector T cells, and therapeutic resistance [80,81].”
Background
Postoperative Natural Killer Cell Dysfunction: The Prime Suspect in the Case of Metastasis Following Curative Cancer Surgery
Market, M., Tennakoon, G., & Auer, R. C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111378 · Cited by 47 · see citing works
“The dual pro- and anti-inflammatory effects of IL-6 are thought to be partially mediated by differences in classical signalling versus trans-signalling [176,183,184].”
Background
The Role of Inflammation in Breast and Prostate Cancer Metastasis to Bone
Göbel, A., Dell'Endice, S., Jaschke, N., Pählig, S., Shahid, A., Hofbauer, L. C., & Rachner, T. D. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105078 · Cited by 45 · see citing works
“CXCR4 on tumor cells, thereby favoring tumor cell proliferation and recruitment to bone via the CXCL12/CXCR4 axis [193,194].”
Background
CAA-derived IL-6 induced M2 macrophage polarization by activating STAT3
Zhao, C.-R., Zeng, N., Zhou, X.-M., Tan, Y.-F., Wang, Y.-C., Zhang, J., Wu, Y.-P., & Zhang, Q. (2023) · BMC Cancer · doi:10.1186/s12885-023-10826-1 · Cited by 38
“Excessive secretion of IL-6 by tumor cells or mesenchymal cells in TME has been demonstrated to promote tumor growth, metastasis, and therapeutic resistance in multiple tumors, including BC [25, 26].”
Background
Toll-like receptor 2 promotes breast cancer progression and resistance to chemotherapy
Lorenzo, A. D., Bolli, E., Ruiu, R., Ferrauto, G., Gregorio, E. D., Avalle, L., Savino, A., Poggio, P., Merighi, I., Riccardo, F., et al. (2021) · Oncoimmunology · doi:10.1080/2162402x.2022.2086752 · Cited by 38 · see citing works
Cancer-associated cells release citrate to support tumour metastatic progression
Drexler, K., Schmidt, K. M., Jordan, K., Federlin, M., Milenkovic, V. M., Liebisch, G., Artati, A., Schmidl, C., Madej, M. G., Tokarz, J., et al. (2021) · Life Science Alliance · doi:10.26508/lsa.202000903 · Cited by 39 · see citing works
“In support of this, we show that cancer cells deprived of extracellular citrate for 48 h release IL-6, which stimulates angiogenesis and GROs involved in stromal transformation/senescence (Nagasaki et al, 2014; Masjedi et al, 2018).”
Role of inflammatory microenvironment: potential implications for improved breast cancer nano-targeted therapy
Lan, M., Lü, W., Zou, T., Li, L., Liu, F., Cai, T., & Cai, Y. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03696-4 · Cited by 39 · see citing works
Toripalimab, a therapeutic monoclonal anti-PD-1 antibody with high binding affinity to PD-1 and enhanced potency to activate human T cells
Rajasekaran, N., Wang, X., Ravindranathan, S., Chin, D. J., Tseng, S.-Y., Klakamp, S. L., Widmann, K., Kapoor, V. N., Vexler, V. S., Keegan, P., et al. (2024) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-024-03635-3 · Cited by 37 · see citing works
“Proinflammatory cytokines such as IL-6, IL-1α, IL-1β and IL1RA are primarily secreted by activated myeloid cells and play critical roles in an anti-tumor immune response [22, 23] (Fig.”
Background
Interleukin-6-derived cancer-associated fibroblasts activate STAT3 pathway contributing to gemcitabine resistance in cholangiocarcinoma
Kittirat, Y., Suksawat, M., Thongchot, S., Padthaisong, S., Phetcharaburanin, J., Wangwiwatsin, A., Klanrit, P., Sangkhamanon, S., Titapun, A., Loilome, W., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.897368 · Cited by 35 · see citing works
“The inhibitor related to the blockage of IL-6 and IL-6R such as tocilizumab is considered as an effective anti-cancer therapeutic approach (Masjedi et al., 2018).”
Background
The Biological and Biomechanical Role of Transglutaminase-2 in the Tumour Microenvironment
Tempest, R., Guarnerio, S., Maani, R., Cooper, J., & Peake, N. (2021) · Cancers · doi:10.3390/cancers13112788 · Cited by 37 · see citing works
“Production of the pro-inflammatory cytokine Intereukin-6 (IL-6) in the TME has been established to be dependent on TG2 expression [133,134].”
Background
Interleukin-6 in retinal diseases: From pathogenesis to therapy.
Xiao, R.-H., Lei, C., Zhang, Y., & Zhang, M. (2023) · Experimental Eye Research · doi:10.1016/j.exer.2023.109556 · Cited by 34 · see citing works
Physical Exercise Restrains Cancer Progression through Muscle-Derived Factors
Papadopetraki, A., Maridaki, M., Zagouri, F., Dimopoulos, M., Koutsilieris, M., & Philippou, A. (2022) · Cancers · doi:10.3390/cancers14081892 · Cited by 34 · see citing works
“Thus, the over-secretion of IL-6 in TME, not only by the tumor cells themselves [53] but also by cancer-associated macrophages [54], fibroblasts [53], adipocytes [55], or mesenchymal stem cells [56], creates favorable conditions for tumor development and metastasis.”
Background
Potential predictive value of change in inflammatory cytokines levels subsequent to initiation of immune checkpoint inhibitor in patients with advanced non-small cell lung cancer
Lim, J. U., & Yoon, H. K. (2020) · Cytokine · doi:10.1016/j.cyto.2020.155363 · Cited by 35 · see citing works
Regulation of aromatase in cancer
Molehin, D., Rasha, F. A., Rahman, R. L., & Pruitt, K. (2021) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-021-04099-0 · Cited by 36 · see citing works
The Tumor Microenvironment of Primitive and Metastatic Breast Cancer: Implications for Novel Therapeutic Strategies
Zarrilli, G., Businello, G., Dieci, M. V., Paccagnella, S., Carraro, V., Cappellesso, R., Miglietta, F., Griguolo, G., Guarneri, V., Mele, M. L., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218102 · Cited by 38 · see citing works
“IL6 is another important CAF-derived factor in the BC microenvironment, and works by binding to IL-6R on neoplastic cell membranes [16].”
Background
The Effect of Zinc and Melatonin Administration on Lipid Peroxidation, IL-6 Levels, and Element Metabolism in DMBA-Induced Breast Cancer in Rats
Gulbahce-Mutlu, E., Baltacı, S., Menevşe, E., Mogulkoc, R., & Baltacı, A. (2020) · Biological Trace Element Research · doi:10.1007/s12011-020-02238-0 · Cited by 33
Nanomedicine for improvement of dendritic cell-based cancer immunotherapy
Hashemi, V., Farhadi, S., Chaleshtari, M. G., Seashore-Ludlow, B. A., Masjedi, A., Hojjat‐Farsangi, M., Namdar, A., Ajoolabady, A., Mohammadi, H., Ghalamfarsa, G., et al. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106446 · Cited by 44 · see citing works
Self-citation
Interleukin-6 in Hepatocellular Carcinoma: A Dualistic Point of View
Nenu, I., Toadere, T. M., Topor, I., Țichindeleanu, A., Bondor, D. A., Trella, Ș. E., Sparchez, Z. A., & Filip, G. A. (2023) · Biomedicines · doi:10.3390/biomedicines11102623 · Cited by 34 · see citing works
“Generally, the overexpression of IL-6 is associated with poor prognosis and a low survival rate in patients with breast cancer [74].”
The Diverse Function of IL-6 in Biological Processes and the Advancement of Cancer
Zhou, Y., Song, X.-T., Yuan, M.-M., & Li, Y.-L. (2025) · Immune Network · doi:10.4110/in.2025.25.e22 · Cited by 31 · see citing works
“STAT3 is constitutively active in more than 50% of BC, including signals from IL-6, IL-11, LIF, and OSM, all of which are implicated in tumor growth (60).”
Dual STAT‑3 and IL‑6R inhibition with stattic and tocilizumab decreases migration, invasion and proliferation of prostate cancer cells by targeting the IL‑6/IL‑6R/STAT‑3 axis
Méndez-Clemente, A. S., Bravo‐Cuéllar, A., Ochoa, S. G., Santiago‐Mercado, M., Palafox-Mariscal, L. A., Jave‐Suárez, L. F., Ibarra, F. S., Villaseñor-Garcı́a, M. M., Ortiz‐Lazareno, P. C., & Hernández‐Flores, G. (2022) · Oncology Reports · doi:10.3892/or.2022.8349 · Cited by 35 · see citing works
“The role of STAT‑3 in multiple types of disease have been studied to develop a specific treatment to inhibit IL‑6, IL‑6R, glycoprotein‑130, Jak and STAT‑3 (15).”
BackgroundInfluential
Quercetin exerts anti-tumor immune mechanism by regulating IL-6/JAK2/STAT3 signaling pathway to deplete Treg cells.
Liao, Y., Xie, X., Zhang, C., Zhong, H., Shan, L., Yu, P., & Xu, L.-P. (2024) · Toxicon · doi:10.1016/j.toxicon.2024.107747 · Cited by 29 · see citing works
Contribution of adrenergic mechanisms for the stress‐induced breast cancer carcinogenesis
Silva, D., Quintas, C., Gonçalves, J., & Fresco, P. (2022) · Journal of Cellular Physiology · doi:10.1002/jcp.30707 · Cited by 36 · see citing works
New Insights in Gene Expression Alteration as Effect of Paclitaxel Drug Resistance in Triple Negative Breast Cancer Cells.
Jurj, A., Pop, L., Zanoaga, O., Ciocan-Cȃrtiţă, C. A., Cojocneanu, R., Moldovan, C., Raduly, L., Pop-Bica, C., Trif, M., Irimie, A., et al. (2020) · Cellular Physiology and Biochemistry · doi:10.33594/000000246 · Cited by 29
Silencing of p68 and STAT3 synergistically diminishes cancer progression.
Hashemi, V., Ahmadi, A., Malakotikhah, F., Chaleshtari, M. G., Moornani, M. B., Masjedi, A., Sojoodi, M., Atyabi, F., Nikkhoo, A., Rostami, N., et al. (2020) · Life Science · doi:10.1016/j.lfs.2020.117499 · Cited by 29 · see citing works
Self-citation
Retracted
RET signaling in breast cancer therapeutic resistance and metastasis
Pecar, G., Liu, S., Hooda, J., Atkinson, J., Oesterreich, S., & Lee, A. V. (2023) · Breast Cancer Research · doi:10.1186/s13058-023-01622-7 · Cited by 28
“Inflammatory cytokines potentiate RET expression and signaling in breast cancer The tumor microenvironment is a key regulator of cancer development and sustained tumor growth, with the expression of inflammatory cytokines acting as a contributor to carcinogenesis and therapeutic resistance in breast cancer [84, 85] as…”
Background
Tumor associated macrophages in the molecular pathogenesis of ovarian cancer
Yousefzadeh, Y., Hallaj, S., Moornani, M. B., Asghary, A., Azizi, G., Hojjat‐Farsangi, M., Ghalamfarsa, G., & Jadidi‐Niaragh, F. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106471 · Cited by 38 · see citing works
Self-citation
Bone Marrow Adipocytes, Adipocytokines, and Breast Cancer Cells: Novel Implications in Bone Metastasis of Breast Cancer
Liu, C., Zhao, Q., & Yu, X. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.561595 · Cited by 31 · see citing works
“ANGPTL2 and IL-6 enhance the reaction of breast cancer cells to bone-derived CXCL12 through the upregulation of CXCL12 receptor CXCR4 in these cancer cells, respectively (52, 53).”
Background
IL‐6 in the spotlight: From cardiovascular pathophysiology to therapy
Preda, A., Tirandi, A., Leo, G., Vece, D. D., Vilahur, G., Bonaventura, A., Osto, E., Ministrini, S., Kraler, S., Kleinbogard, P., et al. (2025) · European Journal of Clinical Investigation · doi:10.1111/eci.70161 · Cited by 26 · see citing works
“26 Based on this hypothesis, autoimmune disorders and cancer seem to be primarily driven by IL-6 trans-signalling, whereas regenerative and protective activities are mediated by classic IL-6 signalling.”
Tumor Microenvironment On‐A‐Chip and Single‐Cell Analysis Reveal Synergistic Stromal–Immune Crosstalk on Breast Cancer Progression
Ravi, K., Zhang, Y.-N., Sakala, L., Manoharan, T. J. M., Pockaj, B., LaBaer, J., Park, J. G., & Nikkhah, M. (2025) · Advancement of science · doi:10.1002/advs.202413457 · Cited by 26 · see citing works
Interleukin-6 related signaling pathways as the intersection between chronic diseases and sepsis
Yang, J., Yang, L., Wang, Y., Lu, H., Shi, B., Zhang, D., Xu, W., & Cui, D. (2025) · Molecular Medicine · doi:10.1186/s10020-025-01089-6 · Cited by 26 · see citing works
Interleukin-6 Signaling in Triple Negative Breast Cancer Cells Elicits the Annexin A1/Formyl Peptide Receptor 1 Axis and Affects the Tumor Microenvironment
Vecchi, L., Mota, S., Zóia, M. A. P., Martins, I. C., de Souza, J. B., Santos, T., Beserra, A. D. O., de Andrade, V. P., Goulart, L., & Araújo, T. (2022) · Cells · doi:10.3390/cells11101705 · Cited by 26 · see citing works
“IL-6 modulates the proliferation and differentiation of malignant cells [32] and its expression is frequently increased in different tumors including prostate cancer [33] and BC [34].”
Background
Codelivery of BV6 and anti-IL6 siRNA by hyaluronate-conjugated PEG-chitosan-lactate nanoparticles inhibits tumor progression.
Salimifard, S., Kiani, F., Eshaghi, F., Izadi, S., Shahdadnejad, K., Masjedi, A., Heydari, M., Ahmadi, A., Hojjat-Farsangi, M., Hassannia, H., et al. (2020) · Life Science · doi:10.1016/j.lfs.2020.118423 · Cited by 26
Self-citation
Retracted
Enhanced anticancer efficacy of TRAIL-conjugated and odanacatib-loaded PLGA nanoparticles in TRAIL resistant cancer.
Nguyen, T. T. K., Woo, S., Seo, S., Banstola, A., Kim, H., Duwa, R., Vu, A. T., Hong, I.-S., Kwon, T. K., & Yook, S. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.122733 · Cited by 25 · see citing works
ERK5 modulates IL-6 secretion and contributes to tumor-induced immune suppression
Riegel, K., Yurugi, H., Schlöder, J., Jonuleit, H., Kaulich, M., Kirschner, F., Arnold-Schild, D., Tenzer, S., Schild, H., & Rajalingam, K. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-04257-8 · Cited by 25 · see citing works
“Not only cancer cells themselves are considered primary sources of IL-6, but also tumor-associated macrophages (TAMs), MDSCs, and cancerassociated fibroblasts (CAFs) [13, 14].”
Background
Smac mimetics as novel promising modulators of apoptosis in the treatment of breast cancer
Nikkhoo, A., Rostami, N., Hojjat-Farsangi, M., Azizi, G., Yousefi, B., Ghalamfarsa, G., & Jadidi-Niaragh, F. (2018) · Journal of Cellular Biochemistry · doi:10.1002/jcb.28205 · Cited by 25 · see citing works
Self-citation
The Molecular and Genetic Interactions between Obesity and Breast Cancer Risk
Ajabnoor, G. (2023) · Medicina · doi:10.3390/medicina59071338 · Cited by 22 · see citing works
STAT3 as a therapeutic target in the metformin-related treatment
Zhang, W., Li, D., Li, B., Chu, X., & Kong, B. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.109770 · Cited by 25 · see citing works
SCD5-dependent inhibition of SPARC secretion hampers metastatic spreading and favors host immunity in a TNBC murine model
Bellenghi, M., Talarico, G., Botti, L., Puglisi, R., Tabolacci, C., Portararo, P., Piva, A., Pontecorvi, G., Carè, A., Colombo, M., et al. (2022) · Oncogene · doi:10.1038/s41388-022-02401-y · Cited by 24
The Signal Transducer IL6ST (gp130) as a Predictive and Prognostic Biomarker in Breast Cancer
Martínez-Pérez, C., Leung, J., Kay, C., Meehan, J., Gray, M., Dixon, J. M., & Turnbull, A. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11070618 · Cited by 25 · see citing works
Tumour brain: Pretreatment cognitive and affective disorders caused by peripheral cancers
Mampay, M., Flint, M. S., & Sheridan, G. K. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15571 · Cited by 27 · see citing works
“increased serum levels of IL-6 have been demonstrated in various cancers (Masjedi et al., 2018).”
Background
Tumor exposed-lymphatic endothelial cells promote primary tumor growth via IL6
van de Velde, M., Ebroin, M., Durré, T., Joiret, M., Gillot, L., Blacher, S., Geris, L., Kridelka, F., & Noel, A. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.10.020 · Cited by 24
“IL6 is one of the major inflammatory interleukins that has been linked to cancer progression [35,40,41].”
Background
Exercise-Mediated Skeletal Muscle-Derived IL-6 Regulates Bone Metabolism: A New Perspective on Muscle–Bone Crosstalk
Zhu, C., Ding, X., Chen, M., Feng, J., Zou, J., & Zhang, L. (2025) · Biomolecules · doi:10.3390/biom15060893 · Cited by 17 · see citing works
CircTMC5 promotes gastric cancer progression and metastasis by targeting miR-361-3p/RABL6
Xu, P., Xu, X.-L., Wu, X., Zhang, L.-X., Meng, L., Chen, Z.-M., Han, W.-X., Yao, J., & Xu, A. (2021) · Gastric Cancer · doi:10.1007/s10120-021-01220-6 · Cited by 23 · see citing works
NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment
Reynaud, D., Nahed, R. A., Lemaître, N., Bolze, P., Traboulsi, W., Sergent, F., Battail, C., Filhol, O., Sapin, V., Boufettal, H., et al. (2021) · Cancers · doi:10.3390/cancers13122999 · Cited by 23
Interlinking pathways: a narrative review on the role of IL-6 in cancer and atherosclerosis
Cau, R., & Saba, L. (2023) · Cardiovascular Diagnosis and Therapy · doi:10.21037/cdt-24-344 · Cited by 22 · see citing works
“IL-6 is involved in various aspects of cancer development, including cell proliferation, survival, angiogenesis, and metastasis, and has been linked to a poor prognosis in several cancer types (8,31,39-44) ( Table 3 ).”
Formulation and Characterization of Doxycycline-Loaded Polymeric Nanoparticles for Testing Antitumor/Antiangiogenic Action in Experimental Colon Cancer in Mice
Alshaman, R., Alattar, A., El-Sayed, R. M., Gardouh, A. R., Elshaer, R. E., Elkazaz, A., Eladl, M., El-Sherbiny, M., Farag, N., Hamdan, A., et al. (2022) · Nanomaterials · doi:10.3390/nano12050857 · Cited by 22 · see citing works
Oleuropein-Rich Leaf Extract as a Broad Inhibitor of Tumour and Macrophage iNOS in an Apc Mutant Rat Model
Ruzzolini, J., Chioccioli, S., Monaco, N., Peppicelli, S., Andreucci, E., Urciuoli, S., Romani, A., Luceri, C., Tortora, K., Calorini, L., et al. (2021) · Antioxidants · doi:10.3390/antiox10101577 · Cited by 25 · see citing works
Advances in tumor-associated macrophage-mediated chemotherapeutic resistance in glioma
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BackgroundInfluential
Interleukin-6 transiently promotes proliferation of osteoclast precursors and stimulates the production of inflammatory mediators
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Background
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Background
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Authors: Masjedi, A., Hashemi, V., Hojjat-Farsangi, M., Ghalamfarsa, G., Azizi, G., Yousefi, M., & Jadidi-Niaragh, F.
Affiliations: Tabriz University of Medical Sciences (IR)
University of Maragheh (IR)
Yasuj University of Medical Sciences (IR)
Alborz University of Medical Sciences (IR)
ORCID: Masjedi, Ali
Hashemi, Vida
Hojjat-Farsangi, Mohammad
Ghalamfarsa, Ghasem
Azizi, Gholamreza
Yousefi, Mehdi
Jadidi-Niaragh, Farhad
Venue: Biomedicine & Pharmacotherapy
Publisher: Elsevier BV
Published: 2018-12
Volume: 108
Pages: 1415-1424
ISSN: 0753-3322 (ISSN-L)
DOI: 10.1016/j.biopha.2018.09.177
OpenAlex: W2894776217
Cited by: 303
References: 136
Citations by year: 2026: 20 · 2025: 33 · 2024: 32 · 2023: 60 · 2022: 67 · 2021: 41 · 2020: 39 · 2019: 9 · 2018: 1
FWCI: 2.37
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Biomedicine & Pharmacotherapy (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Funders: National Institute for Medical Research Development
Topics: Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords: interleukin-6, IL-6 signaling, breast cancer, tumor microenvironment, chronic inflammation, cancer-associated fibroblasts, chemoresistance, radioresistance (biology), metastasis, immunopathogenesis, combination therapy
MeSH terms: Janus Kinase Inhibitors, Interleukin-6 Inhibitors, Antibodies, Monoclonal, Breast Neoplasms, Female, Humans, Signal Transduction, Interleukin-6, Receptors, Interleukin-6, Tumor Microenvironment, Antibodies, Monoclonal, Humanized

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The significant role of interleukin-6 and its signaling pathway in the immunopathogenesis and treatment of breast cancer

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